Using rodent model systems, studies have been carried out to determine why certain retroviruses cause neurological disease. PVC-211 murine leukemia virus (MuLV) is a neuropathogenic variant of Friend MuLV that causes neurodegenerative disease in susceptible mice and rats. We have previously shown that PVC-211 MuLV is significantly more infectious to brain capillary endothelial cells (BCEC) than Friend MuLV and that there is a correlation between endothelial cell tropism of the virus and its neuropathogenicity. We have also shown that the major determinant responsible for endothelial cell tropism, and thus neuropathogenicity, is localized to the SU protein coding region of the envelope gene of PVC- 211 MuLV. To test the possibility that BCEC tropism of PVC-211 MuLV results from a unique virus-receptor interaction on BCEC, we compared the infectivity of PVC-211 MuLV and other MuLVs on a permanent cell line derived from a primary culture of rat BCEC. Although this cell line expresses a high level of mRNA for the ecotropic MuLV receptor, only PVC- 211 MuLV could efficiently infect these cells. Further studies indicated that the failure of F-MuLV and other MuLVs to efficiently infect BCEC was due to a glycosylation-dependent modification of the viral receptor on these cells. Studies utilizing chimeric viruses between PVC-211 MuLV and Friend MuLV showed that as few as two amino acid differences in the N- terminal half of its SU envelope protein were responsible for the BCEC tropism of PVC-211 MuLV. Thus, changes in the envelope gene of PVC-211 MuLV have enabled it to enter the central nervous system by efficiently infecting endothelial cells in the brain via a modified or unique receptor. BCEC derived from resistant animals could still be infected with PVC-211 MuLV in vitro, indicating that resistance was not at the level of the target cell. The unusual endothelial cell tropism of PVC- 211 MuLV was also shown to extend to endothelial cells outside of the brain, making the virus a promising vector for gene transfer studies targeting endothelial cells.